The cerebellar vermis and midline cerebellum contribute to motor, oculomotor, vestibular, cognitive, affective, autonomic, and network-level functions. Human rTMS/TBS studies targeting these regions are methodologically heterogeneous, and reported effects may be over-attributed when anatomical labels, localization methods, or target separability are unclear. We conducted a PRISMA-ScR-guided scoping review of human repetitive transcranial magnetic stimulation and theta-burst stimulation studies targeting the cerebellar vermis or midline cerebellum. PubMed/MEDLINE, Scopus, Web of Science Core Collection, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP) were searched from inception to 6 August 2026, with no publication-date restriction. Evidence was synthesized by functional domain, methodological characteristics, and a pragmatic target-interpretability framework based on anatomical labeling, localization, condition separability, and reporting adequacy. Forty-eight studies met the eligibility criteria. Evidence spanned ten functional domains or application-oriented areas and was heterogeneous in populations, protocols, localization, comparator or sham procedures, outcome timing, and adverse-event reporting. Twenty-six studies used direct vermis/midline targets, 12 provided separately interpretable vermis/midline conditions, and 10 used lower-specificity medial/paravermal or midline-related targets. Trial-registry searching yielded 243 unique registrations, identifying ongoing and unpublished studies that contextualize the evidence map; however, no additional study entered the primary synthesis from registry alone. The review contributes a functional evidence map, a pragmatic framework for anatomical attribution, and an author-proposed minimum reporting checklist derived from mapped methodological gaps. The literature supports broad functional investigation of vermal and midline stimulation, but not established therapeutic efficacy. Future studies require more precise targeting, reproducible reporting, rigorous controls, and domain-specific replication.
Background/Objectives: The Cerebellar Cognitive-Affective Syndrome (CCAS) scale, introduced by Schmahmann, was prospectively administered to 73 symptomatic Chiari malformation type I (CM1) patients (17 pediatric) to assess cerebellar contribution to cognitive-affective dysfunction and evaluate the utility of a cerebellar-focused screening tool. Methods: CCAS was categorized as possible (1 failed test), probable (2 failed tests), or definite (≥ 3 failed tests). CCAS total and subtest scores were correlated with baseline symptoms (n = 73) and standard neuropsychological batteries (WAIS, PROMIS, D-KEFS, WRAT, and CVLT, n = 34) using Pearson product–moment correlation with Bonferroni correction. General-linear- model ANOVAs evaluated CCAS diagnostic categories and postoperative outcomes (Chicago-Chiari-Outcome Scale, n = 43). Results: Definite CCAS was identified in 44
Chiari malformation type I (CM1) is traditionally viewed as a structural disorder of the posterior fossa characterized by cerebellar tonsillar herniation. However, growing evidence indicates that CM1 is frequently accompanied by disturbances in cognition, emotion, and behavior that cannot be fully explained by pain, hydrocephalus, or radiographic severity alone. Advances in cerebellar neuroscience highlight the cerebellum’s critical role in higher-order cognition and affect through distributed cerebrocerebellar networks. Here, we synthesize neuropsychological, neuroimaging, developmental, and clinical evidence to reframe CM1 as a disorder of cerebellar cognitive affective dysfunction. Across pediatric and adult populations, CM1 is associated with domain-specific inefficiencies in attention, executive control, working memory, visuospatial processing, language fluency, and social cognition, closely paralleling the cerebellar cognitive affective syndrome (CCAS). Network-level imaging studies further demonstrate disruption of cortico-ponto-cerebellar and cerebello-thalamo-cortical connectivity, supporting a distributed rather than focal model of disease. We highlight the modulatory roles of development and chronic pain, critically evaluate cognitive outcomes after posterior fossa decompression, and discuss implications for assessment and future research. Recognizing CM1 as a disorder of cerebellar network integration has important consequences for clinical care and mechanistic investigation.
Background: Spinocerebellar ataxia type 6 (SCA6) has traditionally been classified as a "pure" cerebellar syndrome; however, converging evidence points to non-motor involvement. Characterization of its cognitive-affective profile remains limited, constraining the understanding of its full clinical spectrum. Objectives: To investigate non-motor manifestations in SCA6 and contribute to a more comprehensive characterization of its cognitive-affective profile through standardized neuropsychological assessment. Methods: A monocentric, cross-sectional case-control study included nine patients with genetically confirmed SCA6 and eight healthy controls matched for age and years of education. Participants were assessed using the Cerebellar Cognitive Affective/Schmahmann Syndrome Scale (CCAS-S), the Scale for the Assessment and Rating of Ataxia (SARA), and a comprehensive neuropsychological battery. Anxiety and depressive symptoms were also assessed. Results: Compared with controls, SCA6 patients showed poorer performance on time-dependent measures sensitive to inhibitory control and selective attention and on tasks involving visuoconstructive and visuomotor integration, as well as poorer verbal episodic memory, with a trend toward poorer confrontation naming; motor slowing and reduced processing speed cannot be ruled out. Anxiety was significantly elevated. Cerebellar motor dysfunction predicted a higher number of failed CCAS-S domains, even after controlling for disease duration. Conclusions: These exploratory findings suggest cognitive and affective alterations in SCA6 beyond the motor domain, warranting investigation within the Cerebellar Cognitive Affective Syndrome framework. Given the small sample, absence of correction for multiple comparisons, and potential motor and processing-speed confounds, results are preliminary. They highlight the relevance of targeted neuropsychological assessment and may inform more individualized care strategies.
Primary familial brain calcification (PFBC) is a rare inherited neurological disorder characterized by bilateral intracranial calcifications and heterogeneous clinical manifestations. MYORG-related PFBC is a recently identified autosomal recessive subtype; however, its metabolic abnormalities and dopaminergic function remain incompletely characterized. We report a 45-year-old man with progressive parkinsonism, dysarthria, and a history of recurrent limb twitching. Genetic analysis identified a novel homozygous frameshift variant in MYORG (c.348_352dup, p.Gly118AlafsTer76), confirming the diagnosis of MYORG-related PFBC. Multimodal positron emission tomography (PET), including fluorine-18 fluorodeoxyglucose (18F-FDG) PET and fluorine-18 fluoropropyl-carbomethoxy iodophenyl tropane (18F-FP-CIT) PET, was performed to assess cerebral glucose metabolism and presynaptic dopaminergic function. 18F-FDG PET demonstrated reduced metabolism in the right caudate nucleus and cerebellum, whereas 18F-FP-CIT PET showed preserved striatal dopamine transporter availability. These findings suggest that parkinsonian symptoms in this patient with MYORG-related PFBC may be associated with dysfunction of the striato-cerebellar pathways rather than presynaptic nigrostriatal degeneration. This case expands the genetic spectrum of MYORG-related PFBC and highlights the potential value of combined metabolic and dopaminergic PET imaging for evaluating movement disorders associated with PFBC.
Objectively quantifying cerebellar motor dysfunction remains a challenge in clinical trials. The Adaptability Index, derived from the Prism Adaptation Test, evaluates motor learning but lacks multicenter validation. We aimed to validate the Adaptability Index as a robust biomarker across multiple hospitals and investigate its relationship with the Scale for the Assessment and Rating of Ataxia. We enrolled 74 patients with cerebellar degeneration across seven hospitals using a standardized touchscreen system. We analyzed the correlation between Adaptability Index and the Scale for the Assessment and Rating of Ataxia and evaluated inter-hospital robustness using Linear Mixed-effects Modeling. Consistency of Adaptability Index variance between distinct genotypes (Spinocerebellar Ataxia type 6 and type 31) was assessed using Levene’s test and normalized standard deviations. The Adaptability Index correlated negatively with the Scale for the Assessment and Rating of Ataxia (r = − 0.364, p < 0.01). Notably, Linear Mixed-effects Modeling revealed negligible inter-hospital variance, confirming robustness against site-specific biases. Levene’s test indicated consistent Adaptability Index variance across these genotypes (p = 0.41). However, the Adaptability Index exhibited higher resolution than the Scale for the Assessment and Rating of Ataxia in detecting phenotypic variability (larger normalized standard deviations), particularly in the Spinocerebellar Ataxia type 31 cohort, likely reflecting cerebellar motor learning capacity distinct from motor execution deficits. The Adaptability Index is a valid, genotype-stable, and site-independent biomarker of cerebellar motor learning. Its high resolution and robustness make it a promising objective endpoint for multicenter interventional trials targeting cerebellar dysfunction.
The cerebellar nuclei form the main output structures of the cerebellum and are composed of a deeply conserved set of cell types. Two excitatory cell classes, Class-A and -B, are present in each cerebellar nucleus and mediate all excitatory output of the cerebellum. To provide genetic access to these cell types, here we identified Acan as a marker gene for Class-B cells and generated a knock-in Acan-P2A-Cre mouse line. We demonstrate that this Acan-Cre line selectively labels Class-B neurons in the cerebellar nuclei and validate its use in viral projection tracing. This new mouse line provides a valuable genetic tool to study cerebellar nuclei organization and function.
Ankylosing spondylitis (AS) is a chronic immune-mediated inflammatory disease primarily affecting the axial skeleton and is frequently associated with postural instability, impaired balance, and altered motor control. The cerebellum plays a central role in sensorimotor integration; however, cerebellar volumetric alterations in AS remain insufficiently elucidated. This study aimed to investigate cerebellar and cerebellar lobular volumetric changes in individuals with AS using a fully automated magnetic resonance imaging (MRI) segmentation method. This retrospective study included 15 patients with AS and 15 age- and sex-matched healthy controls (HC). Brain MRI data were analyzed using the automated CERES pipeline of the volBrain platform. All cerebellar volumetric measures were normalized to intracranial volume (ICV). Group comparisons were performed using appropriate parametric and non-parametric tests, and multiple comparisons were controlled using the false discovery rate (FDR) method. Compared with the control group, nominal differences (p < 0.05) were observed in several cerebellar regions, including Lobule V, Lobule VI, and Lobule VIIIA. Similarly, nominal differences were identified in the gray matter volumes of Lobule I–II and Lobule VIIIA. However, none of these findings remained statistically significant after FDR correction (all q > 0.05). Cerebellar volumetric differences in AS appear to be subtle and do not remain significant after correction for multiple comparisons. These findings suggest that previously reported differences may reflect inter-individual variability rather than robust disease-specific structural alterations. Further studies with larger cohorts and multimodal approaches are warranted.
Spinocerebellar ataxia type 8 (SCA8) is traditionally characterized as a cerebellar syndrome, yet emerging evidence suggests significant phenotypic heterogeneity. The complex non-linear relationship between genetic burden and clinical severity remains understudied. We analyzed 172 SCA8 patients using advanced data mining techniques. Complete clinical demographic data were available for the cohort, with precise genetic repeat numbers available for 171 individuals. K-means clustering identified patient subtypes, while Gaussian Graphical Models (GGM) visualized symptom topology. We developed exploratory machine learning models (Decision Tree/Random Forest) and employed Generalized Additive Models (GAM) to characterize non-linear genotype-phenotype dynamics. Clustering identified three distinct phenotypes: Severe Multi-system (12
The cerebellar rhombic lip (RL) of the prenatal hindbrain is a progenitor niche essential for cerebellar glutamatergic neurogenesis. Humans demonstrate a structural elaboration of this niche with a rhombic lip subventricular zone (RL-SVZ). Disruption of this zone causes cerebellar malformations and tumors, yet its gene regulatory networks are poorly understood. We present a predicted gene regulatory network for the human RL inferred from epigenomic maps of the developing human cerebellum. We generated DNA methylomes from microdissected mid-gestation human RL ventricular zone (RL-VZ) and RL-SVZ (N = 9; 15–16 post-conception weeks) using low-input Enzymatic MethylSeq, and profiled histone marks of active promoters and enhancers in whole fetal cerebellum (N = 6; 14 and 18 weeks). Transition from RL-VZ to RL-SVZ is accompanied by widespread hypomethylation, including 9,855 differentially methylated regions (DMRs) enriched for binding sites of ATOH1, NEUROD1/2, and HMGA1. Of these, 88.9
Coordinated locomotion depends on rhythmic neural interactions, with the cerebellum contributing to movement timing and scaling. However, how cerebellar oscillatory dynamics influence human gait remains unclear, despite its relevance for motor learning and rehabilitation. We hypothesized two frequency-dependent effects: (i) gait-matched cerebellar transcranial alternating current stimulation (c-tACS) would produce stronger phase alignment than sham and selectively affect temporal rather than spatial gait parameters; and (ii) higher-frequency stimulation would preferentially modulate spatial gait parameters without consistent phase alignment with the ongoing locomotor rhythm. To test this, fifteen healthy adults received randomized bilateral c-tACS at their individual gait-cycle frequency (iGCF), iGCF ± 10
Oculomotor dysfunction is common in ataxias, but its impact on patient-reported visual function remains insufficiently understood. To characterize patient-reported visual function across ataxias and assess the functional significance of specific oculomotor abnormalities in spinocerebellar ataxias. Participants were recruited at Massachusetts General Hospital (n = 117): 56 with genetically-defined ataxias (SCA2, SCA3, SCA6, SCA27B, CANVAS), and 61 controls. Patient-reported visual function was assessed using a 13-item subset of the Visual Activities Questionnaire targeting depth perception, visual acuity/spatial vision, and visual processing speed. Clinical oculomotor assessments focused on four domains: abnormal eye movements at rest, gaze-evoked nystagmus, ocular pursuit abnormalities, and dysmetria of saccades. Clinical severity was assessed with the Brief Ataxia Rating Scale and Modified International Cooperative Ataxia Rating Scale, and subjective symptoms with PROM-Ataxia. Group comparisons, correlations, and regression analyses were performed. All ataxia groups reported significantly worse visual function than controls, with the largest deficits in visual processing speed. Compared with age-matched controls, SCA3 and SCA6 individuals had significantly greater functional impairment across all subcategories. In ataxias, visual function correlated moderately with PROM-Ataxia and weakly with clinical oculomotor scores. Gaze-evoked nystagmus was the only oculomotor sign independently associated with reduced visual function. Ataxias are associated with substantial visual impairment, particularly in visual processing speed. Gaze-evoked nystagmus predicts reduced visual function in ataxias, highlighting the functional relevance of fixation instability. Patient-reported measures of visual function and oculomotor assessments are essential for capturing visual disability in clinical care and trials.
Spinocerebellar ataxia (SCA) is a group of genetic neurodegenerative disorder characterised by progressive cerebellar and associated structural dysfunction. The prevalence of SCA subtypes are considerably variation among different ethnic groups and regions. However, the relative frequencies of these SCA subtypes remain understudied in northern Chinese populations. The study aimed to characterise the geographical heterogeneity of SCA subtypes between northern and southern China. We retrospectively analysed the genotypes and the clinical features of SCA patients primarily from northern China in Beijing Tiantan Hospital over the past five years. We compared the relative frequencies of subtypes found in the northern cohort with those reported in southern China. A total of 105 unrelated Chinese families were genetically verified, comprising 80 families from northern China and 25 families from southern China. Among the 80 families from northern China, SCA3 was identified in 46 families (57.5
The cerebellum, long known for its role in motor control, has increasingly been implicated in cognitive and affective functions. Despite this broadened perspective, its connectivity remains undercharacterized relative to the cerebral cortex. Here, we present the first comprehensive cerebellar connectome analysis derived from a large-scale, meta-analytic database of over 7,800 high-resolution tract-tracing studies in the rat brain. Leveraging the neuroVIISAS framework, we constructed a directionally weighted, hierarchically organized cerebellar subnetwork integrating both intrinsic and extrinsic connections, including lateralization and interhemispheric projections. Our methodological pipeline involved region expansion, graph-theoretical filtering, and systematic edge weighting by anatomical significance. The resulting network, encompassing 862 regions and over 21,000 edges, was analyzed across multiple topological scales. Mesoscale analysis revealed hallmark properties of small-world and scale-free networks, while motif and modularity analyses identified non-random, functionally coherent microcircuits and subsystems. Local connectome metrics uncovered key integrative hubs–especially within brainstem-cerebellar loops–and exposed gradients of modularity, controllability, and vulnerability. A novel vulnerability analysis showed that the removal of high-significance edges leads to rapid and irregular degradation of clustering in the empirical network, in contrast to the robustness of rewired surrogate models. This indicates the presence of structurally privileged bottlenecks essential for cerebellar integration. Our results collectively highlight the cerebellum’s dual design: functionally specialized yet structurally efficient, with both local modularity and long-range integration. This study establishes a robust foundation for future multimodal, dynamic, and cross-species connectomic research. Integrating empirical data on neuronal dynamics, synaptic plasticity, and gene expression will be essential to fully realize the translational potential of cerebellar network models in both health and disease.
Aphasia is a language impairment resulting from stroke. While numerous studies have explored the association between supratentorial white matter damage and post-stroke aphasia using diffusion tensor imaging (DTI), the role of infratentorial structures, particularly the cerebellum, remains underinvestigated. Evidence suggests that the cerebellum may play a supportive role in language processing, but its contribution across different aphasia types is not well understood. This study aimed to explore cerebellar white matter involvement in individuals with Broca's, conduction, and anomic aphasia using DTI. Using OpenNeuro data from 155 post-stroke patients, including patients with Broca's, anomic, and conduction aphasia, we examined cerebellar DTI metrics in relation to language function assessed by the Western Aphasia Battery (WAB). We examined the association between WAB scores and DTI findings using a linear regression model adjusted for age at onset and sex. Our study observed a significant difference among three groups of post-stroke patients with aphasia regarding their performance on the WAB test. Unlike individuals with conduction and anomic aphasia, post-stroke patients with Broca's aphasia exhibited associations between QA (Quantitative Anisotropy) and RDI (Restricted Diffusion Imaging) in the superior,middle, and bilateral inferior cerebellar peduncles with WAB-AQ. However, these associations did not remain significant after FDR correction. These findings suggest a potential role for cerebellar pathways in language impairment in post-stroke Broca's aphasia. Future research should apply advanced imaging and broader language assessments to clarify the role of the cerebellum in aphasia severity.
The future of cerebellar stimulation should be moving out of the well-resourced research environment, so implementation needs to expect regulation, home-based models, and popular trust. An example of how a change in policy can affect the feasibility, cost and innovation schedule is the European reclassification of some non-medical NIBS devices as Class III medical devices [1]. There is also evidence in the literature of stakeholder research suggesting that parties concerned with the perceived benefit, with safety and with fear of misuse, affect the acceptability-variables that can dictate trial participation and ultimate adoption.
Autosomal recessive spinocerebellar ataxia type 4 (SCAR4), caused by biallelic vacuolar protein-sorting 13D (VPS13D) variants, is a rare, clinically heterogeneous disorder. To describe an adult-onset SCAR4 case with a 30-year course and compare its features to those of published cases. We analyzed the clinical and imaging findings of a 58‑year‑old man and performed a literature review with pooled analysis of reported VPS13D/SCAR4 cases. The patient developed gait disturbance in his twenties, followed by progressive cerebellar and sensory ataxia, pyramidal signs, and peripheral neuropathy. MRI showed mild cerebellar atrophy. Fluorodeoxyglucose positron emission tomography and brain perfusion single-photon emission computed tomography revealed slightly reduced signals in the anterior cerebellum. Whole-exome sequencing revealed compound heterozygous VPS13D variants, including a pathogenic frameshift and a likely pathogenic missense variant. A literature review identified 47 cases. SCAR4 should be considered in sporadic adults with cerebellar ataxia, pyramidal signs, and peripheral neuropathy.
Episodic ataxia type 2 (EA2) is an autosomal dominant channelopathy caused by CACNA1A mutations, typically presenting with recurrent episodes of ataxia, vertigo, and hemiplegic migraine, often with a normal brain MRI or cerebellar atrophy. This report describes a 47-year-old man with a 22-year history of recurrent severe headaches, limb weakness, truncal ataxia, sensory disturbances, and profound fatigue, triggered by stress or minor trauma. Interictal recovery was complete, but serial MRI revealed extensive T2/FLAIR white matter hyperintensities, initially raising concern for multiple sclerosis or cerebral vasculitis. Lumbar puncture was unremarkable. Genetic testing identified a pathogenic heterozygous CACNA1A variant (c.7411 C > T, p.R2471*), confirming EA2. Symptomatic management with acetazolamide and trigger avoidance improved episode frequency and severity. This case highlights the diagnostic challenges of EA2 when MRI shows atypical white matter lesions and emphasizes the value of genetic testing in atypical presentations. Recognizing these findings can prevent misdiagnosis, guide targeted therapy, and inform family counseling. Pearls: · The variability of CACNA1A- related disorders is broad and continues to expand. The gene-phenotype spectrum includes episodic ataxia type 2 (EA2), familial hemiplegic migraine type 1 (FMH1), sporadic hemiplegic migraine (SHM), spinocerebellar ataxia type 6, epilepsy and developmental epileptic encephalopathy. · Patients with episodic ataxia type 2 have either a normal MRI or cerebellar atrophy, mainly at the vermis. · Episodic ataxia type 2, may be treated with acetazolamide and 4-aminopyridine. Oysters: · EA2 may present in the absence of family history. · It is very common for patients with EA2, to be erroneously diagnosed with another disorder, and the disease is very infrequent. · CACNA1A associated diseases may present with clinical overlap.
Spinocerebellar ataxia type 27B is a recently described autosomal dominant, late-onset cerebellar ataxia caused by an intronic GAA repeat expansion in the fibroblast growth factor 14 (FGF14) gene. Despite being recognized as a frequent adult-onset ataxia, its full clinical spectrum remains incompletely understood. To characterize the neurological, cognitive, and paraclinical phenotype of patients with heterozygous FGF14 repeat expansions (>200) and expand the currently known motor and non-motor features, as well as to assess the co-occurrence of other repeat expansions. In this cross-sectional single-center study, patients with heterozygous FGF14 repeat expansions underwent standardized neurological examination and cognitive screening. Paraclinical data were reviewed when available. 18 patients were included in the study (mean age at onset: 64 [37–79], at examination: 76 [61–94]). They all presented with gait ataxia, most commonly a lateral veering gait with corrective sidesteps. In addition to the core known cerebellar phenotype, we identified other movement-disorder manifestations, including myokymia, myoclonus, dystonia, and parkinsonism, with nigrostriatal degeneration confirmed in one patient. Cognitive impairment was common, with two-thirds of patients fulfilling criteria for cerebellar cognitive–affective syndrome (mean MoCA: 25 [21–29], CCAS: 86.9/120 [62–108]). Worse CCAS and MoCA performance was associated with increasing ataxia severity. FGF14 repeat expansions ranged from 210 to 520, and co-occurrence with heterozygous expansions in RFC1 or ATXN8/ATXN8OS were identified in three patients. Earlier diagnostic misclassification as transient ischemic attack was reported in 33
Hereditary ataxias are rare cerebellar disorders. Population level mortality patterns in the United States in the previous decades remain insufficiently described. We quantified national mortality trends associated with hereditary ataxias and described stratified trends by sex, race, census region, and urbanization. We analyzed U.S. Multiple Cause of Death data from CDC WONDER for 2000 to 2020. Decedents were identified using ICD-10 code G11 for hereditary ataxias. Age-adjusted mortality rates (AAMRs) per 100,000 were computed using the 2000 U.S. standard population, with 95
